Vibrio cholerae causes the disease cholera, characterized by profuse watery diarrhea which can result in severe dehydration and circulatory collapse in adults. To date, seven pandemics of cholera have been recorded. Until recently only serogroup 01 was implicated in epidemic disease while other serogroups (non-01 V. cholerae) caused only sporadic disease. However, we have been forced to reevaluate the epidemic potential of non-0l strains in light of the recent epidemic of severe cholera-like disease in Bangladesh and India due to a toxigenic non-01 strain (0139 synom. Bengal). The rapid spread of this outbreak and lack of existing immunity suggests that this 0139 strain has the potential to start an eighth pandemic. Non-0l strains, unlike 01 strains, are frequently encapsulated. This has been shown to be important in the pathogenesis of non-01 strains and is involved in their ability to cause extaintestinal disease. Strains from the new epidemic are encapsulated which has profound implications for vaccine development. We propose to examine the role of the 0139 synom. Bengal capsule in the immune response and pathogenesis of these strains, using animal models. Based on our extensive experience with non-01 V. cholerae capsules, we will construct acapsular mutants and compare pathogenesis and immunogenicity of encapsular and mutant strains. We will also examine the role of the capsule in immunogenicity with particular emphasis on its ability to induce protective antibody (using a capsular polysaccharide- protein conjugate vaccine) or mask of antigens. We will also examine the ability of these strains to disseminate from the gastrointestinal tract as this has important implications in vaccine safety and antigen processing. Finally we will begin to examine antigen processing and mucosal priming. Data generated in this project will identify differences in pathogenesis and immunogenicity between 0139 synom. Bengal and 01 V. cholerae strains and will provide a firm foundation for future vaccine development.